Total Synthesis of the Ristocetin Aglycon
A R T I C L E S
Herein we provide full details of the first total synthesis of
the ristocetin aglycon (2).17 The aglycon 2 differs from that of
teicoplanin18 in subtle ways and more significantly from that
of vancomycin,3 both of which have been the subject of recent
synthetic efforts.18-22 The ristocetin aglycon possesses the
identical tetracyclic ring system of teicoplanin18 but lacks the
C and E ring aryl chlorides that are also characteristic of the
vancomycin structure. This removes the element of atropisomer
stereochemistry in the CD and DE ring systems, simplifying
the synthetic challenge of their construction. Unlike teicoplanin,
3
ristocetin incorporates an additional C6 aryl methyl group on
2
the F ring as well as a sensitive C3 â-hydroxy group within
the E subunit like that found in vancomycin. Like teicoplanin,
ristocetin contains a 14-membered diaryl ether FG ring system
not found in vancomycin, which incorporates a racemization
3
prone phenylglycine residue (C2 ), making it a more challenging
synthetic target than vancomycin.
The approach to the ristocetin aglycon was based largely on
our second generation total synthesis of the teicoplanin agly-
con.18 Thus, the aglycon was to be assembled in a highly
convergent approach from 3 and 4 representing the intact ABCD
(15) McComas, C. C.; Crowley, B. M.; Hwang, I.; Boger, D. L. Bioorg. Med.
Chem. Lett. 2003, 13, 2933.
(16) Ristocetin derivatives: Balzarini, J.; Pannecouque, C.; De Clercq, E.;
Pavlov, A. Y.; Printsevskaya, S. S.; Miroshnikova, O. V.; Reznikova, M.
I.; Preobrazhenskaya, M. N. J. Med. Chem. 2003, 46, 2755. Kobrin, M.
B.; Katrukha, H. S.; Fedorova, G. B. J. Antibiot. 1989, 42, 1441. Barna, J.
C. J.; Williams, D. H.; Williamson, M. P. J. Chem. Soc., Chem. Commun.
1985, 254. Herrin, T. R.; Thomas, A. M.; Perun, T. J.; Mao, J. C.; Fesik,
S. W. J. Med. Chem. 1985, 28, 1371.
(17) Aside from the efforts detailed herein, only Pearson has disclosed studies
deliberately targeting ristocetin: Pearson, A. J.; Heo, J.-N. Org. Lett. 2000,
2, 2987. Pearson, A. J.; Zigmantas, S. Tetrahedron Lett. 2001, 42, 8765.
(18) Teicoplanin isolation: Parenti, F.; Beretta, G.; Berti, M.; Arioti, V. J.
Antibiot. 1978, 31, 276. Structure: Hunt, A. H.; Molloy, R. M.; Occolowitz,
J. L.; Marconi, G. G.; Debono, M. J. Am. Chem. Soc. 1984, 106, 4891.
Barna, J. C. J.; Williams, D. H.; Stone, D. J. M.; Leung, T.-W. C.; Doddrell,
D. M. J. Am. Chem. Soc. 1984, 106, 4895. Total synthesis: Boger, D. L.;
Kim, S. H.; Miyazaki, S.; Strittmatter, H.; Weng, J.-H.; Mori, Y.; Rogel,
O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2000, 122, 7416. Boger,
D. L.; Kim, S. H.; Miyazaki, S.; Mori, Y.; Weng, J.-H.; Rogel, O.; Castle,
S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862. Evans, D. A.;
Katz, J. L.; Peterson, G. S.; Hintermann, T. J. Am. Chem. Soc. 2001, 123,
12411. Teicoplanin atropisomerism: Boger, D. L.; Weng, J. H.; Miyazaki,
S.; McAtee, J. J.; Castle, S. L.; Kim, S. H.; Mori, Y.; Rogel, O.; Jin, Q. J.
Am. Chem. Soc. 2000, 122, 10047.
(19) Vancomycin aglycon: Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.;
Loiseleur, O.; Castle, S. L. J. Am. Chem. Soc. 1999, 121, 3226. Boger, D.
L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin,
Q. J. Am. Chem. Soc. 1999, 121, 10004. Vancomycin atropisomerism:
Boger, D. L.; Miyazaki, S.; Loiseleur, O.; Beresis, R. T.; Castle, S. L.;
Wu, J. H.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 8920. Boger, D. L.; Beresis,
R. T.; Loiseleur, O.; Wu, J. H.; Castle, S. L. Bioorg. Med. Chem. Lett.
1998, 8, 721. Boger, D. L.; Loiseleur, O.; Castle, S. L.; Beresis, R. T.;
Wu, J. H. Bioorg. Med. Chem. Lett. 1997, 7, 3199. Boger, D. L.; Castle,
S. L.; Miyazaki, S.; Wu, J. H.; Beresis, R. T.; Loiseleur, O. J. Org. Chem.
1999, 64, 70.
(20) Vancomycin: Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.;
Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Brase, S.; Rubsam, F. Chem.sEur.
J. 1999, 5, 2584. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A.
E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Brase, S.;
Solomon, M. E. Chem.sEur. J. 1999, 5, 2602. Nicolaou, K. C.; Koumbis,
A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughes,
R. Chem.sEur. J. 1999, 5, 2622. Nicolaou, K. C.; Mitchell, H. J.; Jain, N.
F.; Bando, T.; Hughes, R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E.
Chem.sEur. J. 1999, 5, 2648.
Figure 2. Key disconnections.
ring system and the EFG subunit incorporating the preformed
FG ring system, Figure 2. Coupling of 3 and 4 followed by DE
ring closure by a nucleophilic aromatic substitution reaction of
a phenoxide on an o-fluoronitroaromatic would not only
introduce the diaryl ether linkage but also complete the
assemblage of the ristocetin tetracyclic ring system. The key
DE ring closure conducted at this stage was anticipated to benefit
from an apparent preorganization of the substrate resulting in
facile closure under conditions much milder than those required
of vancomycin.23 Offsetting this advantage is the propensity for
3
C2 epimerization under even mildly basic conditions which
might preclude successful implementation of this approach. The
alternatives include coupling the intact ABCD ring system with
an immediate precursor to 4, incorporating an acyclic FG
intermediate. This less convergent approach requires late stage
closure of the FG ring system but proceeds through intermedi-
3
ates less prone to C2 epimerization and with a key DE ring
closure that likely would be less facile. Consequently, it
appeared to be an accessible alternative should difficulties have
arisen with the more convergent first generation approach.
In turn, the ABCD ring system was anticipated to be available
through sequential CD and AB ring closures analogous to our
efforts on vancomycin. Notably, control of the CD atropisomer
stereochemistry is not an issue with ristocetin by virtue of its
lack of a C ring aryl chloride rendering the diastereoselectivity
of a diaryl ether macrocyclization of an o-fluoronitroaromatic
unimportant (activating NO2 is removed). Thus, the stereo-
chemical issues associated with this approach simplified to the
control of the AB atropisomer stereochemistry. We felt this
could be effectively addressed with an anticipated thermo-
dynamic preference for the natural stereochemistry (ca. 3:1) most
(21) Orienticin C aglycon: Evans, D. A.; Barrow, J. C.; Watson, P. S.; Ratz,
A. M.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K. M.; Ellman, J. A.;
Rychnovsky, S. D.; Lacour, J. J. Am. Chem. Soc. 1997, 119, 3419. Evans,
D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C. J. Am.
Chem. Soc. 1997, 119, 3417. Vancomycin aglycon: Evans, D. A.; Wood.
M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew.
Chem., Int. Ed. 1998, 37, 2700. Evans, D. A.; Dinsmore, C. J.; Watson, P.
S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew.
Chem., Int. Ed. 1998, 37, 2704.
(22) Reviews: Boger, D. L. Med. Res. ReV. 2001, 21, 356. Nicolaou, K. C.;
Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999,
38, 2096. Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem.
Rev. 1995, 95, 2135. Evans, D. A.; DeVries, K. M. Drugs Pharm. Sci.
1994, 63, 63.
(23) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J. Org. Chem.
1997, 62, 4721. Boger, D. L.; Borzilleri, R. M.; Nukui, S. Bioorg. Med.
Chem. Lett. 1995, 5, 3091.
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